PT  - JOURNAL ARTICLE
AU  - Nagai, Marie
AU  - Ohtani, Hisakazu
AU  - Satoh, Hiroki
AU  - Matsuoka, Sayo
AU  - Hori, Satoko
AU  - Fujii, Tomoyuki
AU  - Taketani, Yuji
AU  - Sawada, Yasufumi
TI  - Characterization of Transplacental Transfer of Paroxetine in Perfused Human Placenta: Development of a Pharmacokinetic Model to Evaluate Tapered Dosing
AID  - 10.1124/dmd.113.052332
DP  - 2013 Dec 01
TA  - Drug Metabolism and Disposition
PG  - 2124--2132
VI  - 41
IP  - 12
4099  - http://dmd.aspetjournals.org/content/41/12/2124.short
4100  - http://dmd.aspetjournals.org/content/41/12/2124.full
SO  - Drug Metab Dispos2013 Dec 01; 41
AB  - The aim of this study was to determine whether a tapered dosage regimen of paroxetine in pregnant women might be useful to avoid withdrawal syndromes in neonates after delivery. We characterized the transplacental transfer of paroxetine in perfused human placenta, fitting a pharmacokinetic model to the results and applying the model and parameters to evaluate a tapered dosage regimen. Paroxetine was perfused from the maternal or fetal side of an isolated human placental preparation with various perfusion protocols, and paroxetine concentrations in the effluent and placental tissue were determined. The transplacental pharmacokinetic parameters of paroxetine were estimated by simultaneous fitting of a five-compartment transplacental pharmacokinetic model to the set of paroxetine concentration profiles. The developed model and parameters were used to simulate the maternal and fetal concentrations of paroxetine, and the results were compared with reported data. Paroxetine showed a larger distribution volume in placental tissue and a smaller transplacental transfer as compared with antipyrine, a passive diffusion marker. A five-compartment model could well describe the transplacental transfer of paroxetine and could well simulate the maternal and umbilical venous concentrations of paroxetine at delivery. Transplacental transfer kinetic parameters of paroxetine were estimated by fitting a pharmacokinetic model to perfusion study data. The model and parameters appeared to be suitable for simulation of paroxetine kinetics in fetus. The model was also applicable to design a dosage regimen to avoid an abrupt decrease of paroxetine concentration in fetal plasma.